Esters of monoiodinated benzoyloxyalkanoic acids



United States Patent ESTERS OF MONOIODINATED BENZOYLOXY- This inventionrelates to esters of iodinated benzoic acids, and in particular isconcerned with aliphatic esters of monoiodinated benzoyloxyalkanoicacids.

The preferred aspect of the invention relates to com pounds of theformula wherein R is a member of the group COIlSisting of loweralkyl,lower-alkenyl, lower-alkoxy-lower-alkyl and loweralkylthio-lower-alkyl;R is a member of the group consisting of hydrogen and lower-alkoxy; n isan integer from 2 to 7; and the iodine atom is in a position selectedfrom meta and para with respect to the carboxyl group.

In the above Formula I, the group R preferably contains from one toabout eight carbon atoms and stands for loWer-alkyl, including suchgroups interrupted by oxygen or sulfur, or by a double 'bond(lower-alkenyl). In the above Formula I, the group R, when lower-alkoxy,preferably contains from one to about four carbon atoms. The compoundsof the invention are prepared by either of two general methods asfollows.

(A) Reaction of a substituted benzoyl halide with an ester of a hydroxyacid:

wherein X is halogen, preferably chlorine or bromine, and R, R and nhave the meanings given hereinbefore. The reaction takes place in thepresence of a base such as aqueous alkali or an organic amine, tertiaryamines, such as pyridine or triethylamine, being preferred.

(B) Reaction of a metal salt of a substituted benzoic acid with theester of a halo acid;

wherein M is a metallic cation, preferably an alkali metal, X ishalogen, preferably chlorine or bromine, and R, R and n have themeanings given hereinabove. The reaction takes place either by heatingtogether the reactants directly, or with an inert solvent or reactionmedium, for example dimethylformamide.

The structures of the compounds of the invention were established by themodes of their preparation, their chemical and physical properties, andby the fact that elementary analyses found were in agreement with thevalues calculated for the expected structures.

The compounds of Formula I, including compounds derived from any of themembers of the groups defining R and R, are useful as X-ray contrastmedia, and in particular find application as myelographic agents (i.e.,for visualization of the spinal canal). For this purpose the compoundsin liquid form are injected cisternally into a vertebrate organism. Thisprocedure allows visu: alization of the spinal cord structures. of theinvention possess the advantage of being eliminated from the animalorganism in periods ranging from a few weeks to a few months, whereasmyelographic agents presently in use, such as ethyl10-(p-iodophenyl)undecylate, require much longer periods forelimination.

A few of the compounds of the invention are obtained in the form of lowmelting solids. These however, can be rendered liquid and applicable formyelography by admixture with a physiologically acceptable oil or withanother member of the series which lowersthe melting point below theambient temperature.

The invention is illustrated by but not limited to the followingexamples.

EXAMPLE 1 Method A] Acid chloride and hydroxy-ester in presence ofpyridine Pro pyl 3 3-i0dobenz0yloxy propanoate 3-i0dobenzoyl chloride(61 g.) was added over a period of 3 minutes to ml. of pyridine at 60 C.There was then added over a period of 20 minutes 37.1 g. of propyl3-hydroxy-propanoate in 25 ml. of pyridine with external cooling of thereaction mixture to keep the temperature below 70 C. The reactionmixture was heated at 60- 70 C. for four hours, and after standingovernight was poured into cold water. Concentrated hydrochloric acid wasadded until the mixture had pH 3 and the mixture was extracted withether. The ether extracts were washed with 5% sodium bicarbonatesolution, water and saturated sodium chloride solution, treated withanhydrous calcium sulfate and activated charcoal, and concentrated toremove the volatile solvent. The residue was distilled, collecting thefraction boiling at 129 C. (0.4 nim.), and redistilled, collecting thefraction boiling at 102-104 C. (0.1 mm), to give 22 g. of propyl3-(3-iodobenzoyloxy) propanoate, n =1.5443, viscosity (25 )=28.94centistokes.

EXAMPLE 2 Method A-Z: Acid chloride and hydroxy-ester in presence oftriethylamine A mixture of 53.4 g. of 4-iodobenzoyl chloride, 32.1 g. ofbutyl 3-hydroxypropanoate, 27.4 ml. of triethylamine and 350 ml. ofbenzene was refluxed for 24 hours. The reaction mixture was worked up asdescribed above in Example 1 and the product distilled to give butyl 3-(4-iodobenzoy1oxy)propanoate, B.P. 137 C. (0.08 mm.),

EXAMPLE 3 Method B-1 Sodium salt of acid and halo-ester without solventpropyl 4-(4-i0d0benz0yl0xy)butanoate The compounds '3 is EXAMPLE 4Method B-Z: Sodium salt of acid and halo-ester in dimethylformamideButyl 4- (3-i0d0benz0yl0xy butanoate Sodium 3-iodobenzoate (43.1 g.) and320 ml. of dimethylformamide were heated to 100 C., and after one hour35.6 g. of butyl 4-bromobutanoate was added. The reaction mixture washeated at 110 C. for 24 hours, then poured into ice-Water and extractedwith ether. The ether extracts were washed with water, 5% potassiumcarbonate solution, Water and sodium chloride solution, dried overanhydrous calcium sulfate, and concentrated to remove the volatilesolvent. The residue was distilled to give butyl4-(3-iodobenzoyloxy)butanoate, B.P. 142 C. (0.03 mm.), I1D25=1.5389.

The following compounds were also prepared according to the aboveprocedures as indicated.

Example Name of Compound Procedure (5) Propyl3-(4-iodobenzoyloxy)propanoate A-l (6) 2 ethoxyethyl3-(4-iodobenzoyloxy)propaneate A-1 (7) 3-methoxybutyl3-(4-iodobenzoyloxy)propanoate (8) Ethyl 3-(4-iodobenz0yloxy)propanoateA-2 (9) Propyl 2-(4-iodobenzoyloxy)propanoate 13-1 (10) Propyl3-(4-methoxy-3-iodobenzoyloxy)propanoate A (11) Ethyl4-(4-iodobenzyloxy)butanoate B-2 (12) Butyl4-(4-iodobenzoyloxy)butanoate B2 (13) Methyl4-(4-iodobenzoyloxy)butanoate 13-2 (14) 3-methylbutyl 4(4-iodobenzoyloxy)butanoate 13-2 (15) Butyl5-(4-iodobenzoyloxy)pentanoate B2 (16) Tetrahydrofurfuryl 4-(4-iodobenzoyloxy)butanoate B2 (17) 2 -ethoxyethyl 4(4-iodobenzoyloxy)butanoate' 13-2 (18) Z-methoxyethyl4-(4-iodobenzoyloxy)butanoate B-2 (19) Propyl4-(3-iodobenzoyloxy)butanoate B-2 (20) Propyl6-(4-iodobenzoyloxy)hexanoate 3-2 (21) Allyl4-(4-iodobenzoyloxy)butanoate 13-2 (22) Butyl 4(3-io-do-4-methoxybenzoyloxy)butanoate B- (23) 2 butoxycthyl 4(4-iodobenzoyloxy)butanoate 13-2 (24) 2- ethylmercaptoethyl4-(4-iodobenzoyloxy)- butanoate 13-2 (25) Pentyl4-(4-iodobenzoyloxy)butanoate B-2 Physical properties Example B.P." C.M.P. C. 11 Viscosity (mm. Hg) (25) cs.

The following intermediates were used in the foregoing preparations:

Propyl 3-hydroxypropanoate, B.P. 113 C. (29 mm.), 11 =l.4220, preparedfrom B-propiolactone and propanol in the presence of sodium hydroxide.

Butyl 3-hydroxpropanoate, B.P. 52 C. (0.03 mm.), n =1.4275, preparedfrom ,B-propiolactone and butanol in the presence of sodium hydroxide.

Propyl 4-bromobutanoate, B.P. 1131l6 C. (26 mm.), n =1.4536, preparedfrom 4-brom0butanoic acid and propanol in the presence of hydrogenbromide.

Z-Ethoxyethyl 3-hydroxypropanoate, B.P. 66-67 C. (0.05 mm.), r1 =1.4348,prepared from propiolactone and 2-ethoxyethanol in the presence ofsodium hydroxide.

3-methoxybutyl 3-hydroxypropanoate, B.P. C. (0.05 mm.), 11 =1.4371,prepared from propiolactone and 3-methoxy-1-butanol in the presence ofsodium hydroxide.

Ethyl 3-hydroxypropanoate, n =1.4205, prepared from propiolactone andethanol.

Propyl 2-bromopropanoate, B.P. 8486 C. (29 mm.), n =1.4430, preparedfrom a-bromopropionic acid and propanol in the presence of hydrogenchloride.

Ethyl 4-bromobutanoate, B.P. 9798 C. (17 mm.), n =1.4532, prepared from4-bromobutanoic acid and ethanol in the presence of hydrogen bromide.

Butyl 4-bromobutanoate, B.P. 132-133 C. (25 mm.), n =1.4539, preparedfrom 4-bromobutanoic acid and butanol in the presence of hydrogenbromide.

Methyl 4-bromobutanoate, B.P. 87 C. (19 mm.), n =1.4577, prepared from4-bromobutanoic acid and methanol in the presence of hydrogen bromide.

3-methylbutyl 4-bromobutanoate, B.P. 127 C. (14 mm.), n =1.4552,prepared from butyrolactone, isoamyl alcohol and hydrogen bromide.

Butyl S-bromopentanoate, B.P. 134 C. (15 mm.), n =1.4560, prepared from5-bromopentanenitrile and butanol in the presence of sulfuric acid.

Tetrahydrofurfuryl 4-bromobutanoate, B.P. 79 C. (0.04 mm.), n =1.4820,prepared from tetrahydrofurfuryl alcohol and 4-bromobutanoic acid.

2-ethoxyethyl 4-bromobutanoate, B.P. 136-138 C. (12 mm.), n =1.4598,prepared from butyrolactone, 2- ethoxyethanol and hydrogen bromide.

Z-methoxyethyl 4-bromobutanoate, B.P. 129132 C. (12 mm.), n 2s=1.4608,prepared from butyrolactone, 2- methoxyethanol and hydrogen bromide.

Propyl 6-bromohexanoate, B.P. 143 C. (17 mm.), n =1.4525, prepared from6-bromohexanenitrile and propanol in the presence of sulfuric acid.

Allyl 4-chlorobutanoate, B.P. 97 C. (16 mm.), 11 =1.4465, prepared from4-chlorobutanoic acid and allyl alcohol in the presence ofp-toluenesulfonic acid.

2-butoxyethyl 4-chlorobutanoate, B.P. 166 C. (27. mm.), n =1.4411,prepared from 4-chlorobutanoic acid and 2-butoxyethanol in the presenceof p-toluenesulfonic acid.

2-methylmercaptoethyl 4-chlorobutanoate, B.P. C. (27 mm.), n =1.48S 8,prepared from 4-chlorobutanoic acid and 2-methylmercaptoethanol in thepresence of ptoluenesulfonic acid.

Pentyl 4-chlorobutanoate, B.P 118 C. (11 mm.), n =1.4371, prepared from4-chlorobutanoic acid and amyl alcohol in the presence ofp-toluenesulfonic acid.

Following the procedure of Example 4, the sodium salt of4-iodo-2-methoxybenzoic acid or the sodium salt of 3-iodo-4-ethoxybenzoic acid can be caused to react with butyl4-bromobutanoate to give, respectively, butyl 4-(4-iodo-2-methoxybenzoyloxy)butanoate or butyl 4-(3-iodo-4-ethoxybenzoyloxy)butanoate.

Following the procedure of Example 4, the sodium salt of 4-iodobenzoicacid can be caused to react with methyl 7-bromoheptanoate or methyl8-bromooctanoate to give, respectively, methyl7-(4-iodobenzoyloxy)heptanoate or methyl 8-(4-iodobenzoyloxy)octanoate.

5 We claim:

4. A compound of the formula 1. A compound of the formula o-oo 11H2nCOOR I O0oO,.H2,.C OOR wherein R is lower-alkoxy-lower-alkyl and n is aninteger from 2 t0 7.

5. Propyl 3-(4-iodobenzoyloxy)propanoate. 6. Butyl3-(4-iodobenzoyloxy)propanoate. 7. Propyl 4-(4-iodobenzoyloxy)butanoate.

wherein R is a member of the group consisting of loweralkyl,loWer-alkenyl, loWer-alkoxy-lower-alkyl, tetrahy- PTOPYI y--10d0benzoyloxy)propanoate. drofurfuryl and lower-alkylthio-lower-alkyl;R is a mem- Butyl 4(4'l9dobenzoyloxy)butanoateber of the groupconsisting of hydrogen and loWer-alkoxy; Butyl n is an integer from 2 to7; and the iodine atom is in a Butyl 5'(4'lodobenzoyloxy )pentanoate'position selected from meta and para with respect to theTetrahydmfuffuryl 4 (4 d benZOy10Xy)butacarboxyl group. noate' Acompound of the formula 13. 2-butoxyethyl 4-(4-1odobenzoyloxy)butanoate.

14. Z-methylmercaptoethyl 4 (4 iodobenzoyloxy)butanoate. ReferencesCited by the Examiner UNITED STATES PATENTS 3,013,052 12/1961 Richter260471 3,014,927 12/1961 Garber et a1. 260-347.4 Wh r R 1 1k 1 d t 0 f 2t 7 3,073,848 1/1963 Wasson et a1. 260-347.4 e em ower'a Y an m Beer mmo 3,097,229 7/1963 Beaver et a1. 260-471 3. A compound of the formulaOTHER REFERENCES Strain et 'a1., J.A.C.S., vol. 64 (1942), pp. 14364440.

LORRAINE A. WEINBERGER, Primary Examiner. IRVING MARCUS, Examiner.

HENRY R. JILES, SIDNEY B. WILLIAMS, JR.,

Assistant Examiners.

wherein R is lower-alkyl and n is an integer from 2 to 7.

1. A COMPOUND OF THE FORMULA R'',(I-)-PHENYL-COO-CNH2N-COO-R WHEREIN RIS A MEMBER OF THE GROUP CONSISTING OF LOWERALKYL, LOWER-ALKENYL,LOWER-ALKOXY-LOWER-ALKYL, TETRAHYDROFURFURYL ANDLOWER-ALKYLTHIO-LOWER-ALKYL; R'' IS A MEMBER OF THE GROUP CONSISTING OFHYDROGEN AND LOWER-ALKOXY; N IS AN INTEGER FROM 2 TO 7; AND THE IODINEATOM IS IN A POSITION SELECTED FROM META AND PARA WITH RESPECT TO THECARBOXYL GROUP.